Recent clinical trials conducted at the Surgery Branch of the National Cancer Institute (NCI) has have found that adoptive transfer of autologous tumor reactive T cells into patients preconditioned with nonmyeloablative chemotherapy leads to significant durable objective clinical responses. T cells used in these studies were TIL harvested from melanoma lesions. There are two key problems that have limited its use outside the NCI. First, many patients don't have suitable tumors TIL harvest. Second, it is difficult to isolate and expand tumor reactive T cells to therapeutic numbers for most patients. New approaches for adoptive T cell transfer are needed if this approach will make it beyond the experimental stage. We published the first report demonstrating that it was feasible to redirect the reactivity of normal PBL-derived T cells using retroviral vectors encoding TCR genes isolated from a MART-1 reactive T cell clone. This opened the possibility of providing any patient with a source of autologous tumor-reactive T cells capable of recognizing any antigen so long as a TCR was available which could recognize that antigen. This MART-1 reactive TCR was the first used to treat patients with TCR gene modified T cells demonstrating the feasibility and safety of using TCR gene modified T cells in humans. However, this trial and three others had fewer objective clinical response compared to TIL suggesting TCR gene modified T cells are less effective that TIL. Based on these trials, it is clear there are critical differences between these two cells types. Over the years, the field of TCR gene transfer has focused on TCR affinity, TCR pairing, and TCR expression. The biology of T cells engineered with viral vectors has largely been unexplored. We therefore hypothesize that TCR gene modified T cells are fundamentally different than normal T cells in how they respond to environmental factors. We further hypothesize that a better understanding of how TCR transduced T cells are impacted by lymphopenia, T cell help, activation-induced cell death (AICD), costimulation, and immune suppression will lead to better TCR transduced T cells for patient treatment. Based on these hypotheses, we developed this Program to improve the function of TCR gene modified T cells through a series of laboratory comparing TCR transduced T cells to normal T cells bearing the same TCR. When complimented with clinical trials, our highly integrated Program will advance the field of TCR gene transfer leading to their improved therapeutic efficacy not only for patients with melanoma but for patients with other malignancies and chronic viral infections.